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- Title
Antigen Dependently Activated Cluster of Differentiation 8-Positive T Cells Cause Perforin-Mediated Neurotoxicity in Experimental Stroke.
- Authors
Mracsko, Eva; Liesz, Arthur; Stojanovic, Ana; Lou, Wilson Pak-Kin; Osswald, Matthias; Wei Zhou; Karcher, Simone; Winkler, Frank; Martin-Villalba, Ana; Cerwenka, Adelheid; Veltkamp, Roland
- Abstract
Neuroinflammation plays a key role in secondary brain damage after stroke. Although deleterious effects of proinflammatory cytokines are well characterized, direct cytotoxic effects of invading immune cells on the ischemic brain and the importance of their antigendependent activation are essentially unknown. Here we examined the effects of adaptive and innate immune cells-- cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells--that share the direct perforin-mediated cytotoxic pathway on outcome after cerebral ischemia in mice. Although CTLs and NK cells both invaded the ischemic brain, only brain-infiltrating CTLs but not NK cells were more activated than their splenic counterparts. Depletion of CTLs decreased infarct volumes and behavioral deficit in two ischemia models, whereas NK cell depletion had no effect. Correspondingly, adoptive CTL transfer from wild-type into Ragl knock-out mice increased infarct size. Adoptive CTL transfer from perforin knock-out or interferon-y knock-out mice into Ragl knock-out mice revealed that CTL neurotoxicity was mediated by perforin. Accordingly, CTLs isolated from wild-type or interferon-7 knock-out but not from perforin knock-out mice induced neuronal cell death in vitro. CTLs derived from ovalbumin-specific T-cell receptor transgenic mice were not activated and infiltrated less into the ischemic brain compared with wild-type CTLs. Their transfer did not increase the infarct size of Ragl knock-out mice, indicating antigen-dependent activation as an essential component of CTL neurotoxicity. Our findings underscore the importance of antigen-dependent, direct cytotoxic immune responses in stroke and suggest modulation of CTLs and their effector pathways as a potential new strategy for stroke therapy.
- Subjects
STROKE; T cell differentiation; IMMUNE complexes; PERFORINS; NEUROTOXICOLOGY; CYTOTOXIC T cells; LABORATORY mice
- Publication
Journal of Neuroscience, 2014, Vol 34, Issue 50, p16784
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.1867-14.2014